Graft-vs-host disease (GVHD) is a complex immunological process that is classically thought to be due to the recognition of recipient histocompatibility antigens (major and/or minor) by the donor lymphocytes engrafted with the marrow inoculum. Included in the broad definition of GVHD are two separate processes, acute and chronic GVHD, which appear to be mediated by distinct immunobiological mechanisms. Although acute GVHD appears to be directed at MHC antigens and/or minor antigens restricted by MHC determinants, the immunobiology of chronic GVHD remains enigmatic and is thought to include an autoimmune component. Of interest in this regard is the recent description of a severe autoimmune process after syngeneic/autologous BMT and CsA therapy. This disorder is clinically and histologically similar to GVHD after allogeneic BMT, particularly chronic GVHD. These data implicate that histocompatibility differences are not absolute requirements for GVHD but may be due to a dysregulation of self nonself recognition of MHC antigens. In addition, current studies suggest that the effector mechanism and target antigens of chronic and syngeneic/autologous GVHD are similar. The proposed studies in this subproject plan to evaluate the effector mechanisms in acute, chronic and syngeneic GVHD in a rat model with a particular focus on the Vbeta region T cell receptor repertoire. Preliminary data suggest that an autoreactive T cell receptor marked by expression of the Vbeta 8 gene product is prevalent in both syngeneic and chronic GVHD supporting the hypothesis that chronic GVHD includes a syngeneic GVHD component. Other immunologic effects of these regimens will be sought. Specifically we will characterize the effects of thalidomide on adhesion molecules. We will examine this effect in syngeneic and allogeneic transplants and in acute and chronic GVHD. Likewise we will continue to explore rapamycin as a new agent for GVHD. The results from the proposed studies should provide a clearer insight into the immunobiology of GVHD and delineate ideal immunosuppressive approaches that would prevent the appearance of chronic GVHD.